Background: Cyclosporine A (CsA) is widely used for organ transplantation and autoimmune disorders.
However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. The metabolism of CsA has a
close relationship with this disease in renal-transplant patients. However, the metabolic pathways of CsA and its
metabolizing enzymes have rarely been comprehensively reviewed. In this review, we have summarized the specific
metabolic profiles of CsA in humans, especially renal-transplant patients. Moreover, the specific metabolizing enzymes
and the potential roles that CsA metabolism plays in CsA nephrotoxicity were summarized and discussed.
Methods: Electronic databases including PubMed, Web of Science, and Scifinder were searched with the keywords
"Cyclosporine A and metabolism", and "Cyclosporine A and nephrotoxicity", "Cyclosporine A metabolism and
nephrotoxicity". All these studies published until 2018 were included in this review.
Results: The major metabolic pathways of CsA in humans are hydroxylation and N-demethylation. Normally, these
metabolites are relatively less toxic than CsA. However, the metabolism of CsA in the kidneys is much weaker than
that in the liver, which explains why CsA is so toxic to the kidneys. CYP3A families, especially CYP3A4 and
CYP3A5, play an important role in the biotransformation of CsA. Moreover, increased lines of evidence show that
some metabolites (including AM19) associate directly with nephrotoxicity in CsA-treated organ-transplant patients.
Conclusion: The findings of this review help to further understand the metabolic activities of CsA in renal-transplant
patients and cast some light on the mechanisms of CsA nephrotoxicity.